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1.
Life Sci ; 257: 118061, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652137

RESUMO

Obesity is an independent risk factor for the development of chronic kidney disease. The pathophysiology of the obesity-induced kidney injury is complex, but evidence suggests the involvement of reduced adiponectin levels and signaling. We investigated the extent by which adiponectin contributes to the establishment and progression of renal disease in wild type (WT) and adiponectin null (adipoKO) mice fed a control or a high-fat diet (HFD) for 16 weeks. HFD induced obesity, kidney hypertrophy, albuminuria, renal lipid accumulation and decreased nephrin expression in both mice genotypes. Notably, HFD in adipoKO mice exacerbated progression of albuminuria in comparison to WT mice. In addition, lack of adiponectin per se increased kidney weight, reduced nephrin levels, up-regulated Fabp4 expression, reduced Cpt1a expression and increased miR-130 levels in kidney. Our results demonstrate that lack of adiponectin combined with a HFD contributes to accelerated kidney dysfunction.


Assuntos
Adiponectina/genética , Albuminúria/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/complicações , Insuficiência Renal Crônica/fisiopatologia , Albuminúria/genética , Animais , Carnitina O-Palmitoiltransferase/genética , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Insuficiência Renal Crônica/genética
2.
PLoS Genet ; 16(7): e1008785, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628676

RESUMO

To efficiently transform genetic associations into drug targets requires evidence that a particular gene, and its encoded protein, contribute causally to a disease. To achieve this, we employ a three-step proteome-by-phenome Mendelian Randomization (MR) approach. In step one, 154 protein quantitative trait loci (pQTLs) were identified and independently replicated. From these pQTLs, 64 replicated locally-acting variants were used as instrumental variables for proteome-by-phenome MR across 846 traits (step two). When its assumptions are met, proteome-by-phenome MR, is equivalent to simultaneously running many randomized controlled trials. Step 2 yielded 38 proteins that significantly predicted variation in traits and diseases in 509 instances. Step 3 revealed that amongst the 271 instances from GeneAtlas (UK Biobank), 77 showed little evidence of pleiotropy (HEIDI), and 92 evidence of colocalization (eCAVIAR). Results were wide ranging: including, for example, new evidence for a causal role of tyrosine-protein phosphatase non-receptor type substrate 1 (SHPS1; SIRPA) in schizophrenia, and a new finding that intestinal fatty acid binding protein (FABP2) abundance contributes to the pathogenesis of cardiovascular disease. We also demonstrated confirmatory evidence for the causal role of four further proteins (FGF5, IL6R, LPL, LTA) in cardiovascular disease risk.


Assuntos
Doenças Cardiovasculares/genética , Análise da Randomização Mendeliana , Proteoma/genética , Esquizofrenia/genética , Antígenos de Diferenciação/genética , Doenças Cardiovasculares/patologia , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Fator 5 de Crescimento de Fibroblastos/genética , Estudos de Associação Genética/métodos , Humanos , Lipase Lipoproteica/genética , Linfotoxina-alfa/genética , Masculino , Locos de Características Quantitativas , Receptores Imunológicos/genética , Receptores de Interleucina-6/genética , Esquizofrenia/patologia
3.
PLoS One ; 15(6): e0234328, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579617

RESUMO

FABP4 is a candidate gene for carcass and meat quality traits in livestock and poultry. However, the effects of FABP4 have not been examined in the Yanbian yellow cattle, an economically important local cattle breed in China. In this study, we characterized single nucleotide polymorphisms (SNPs) in FABP4 in this cattle breed and their associations with meat quality traits. Six SNPs (referred to as SNP1-6) were identified in FABP4 by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism. The six SNPs were significantly correlated with meat quality traits. In particular, the GG and GA genotypes of SNP1 were significantly associated with water and fat contents and GG and AA genotypes of SNP1 were significantly associated with protein contents (P < 0.05). The fat content and marbling in heterozygous individuals at SNP2-6 were significantly higher than those in wild-type or mutant individuals (P < 0.05), while protein content was significantly higher in wild-type and mutant individuals than in heterozygous individuals (P < 0.05). A gene expression analysis indicated that the lipid metabolism-related genes FABP4, PPARγ, ANGPTL4, and LPL show similar expression patterns with respect to FABP4 genotypes, with the highest levels in wild-type individuals and the lowest levels in mutants. In conclusion, FABP4 SNPs can be used for marker-assisted selection in Yanbian yellow cattle breeding.


Assuntos
Bovinos/genética , Proteínas de Ligação a Ácido Graxo/genética , Metabolismo dos Lipídeos/genética , Animais , China , Feminino , Qualidade dos Alimentos , Expressão Gênica/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Masculino , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Carne Vermelha/análise , Análise de Sequência de DNA/métodos
4.
PLoS One ; 15(6): e0235217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574225

RESUMO

In sheep, polyunsaturated fatty acid (PUFA) supplementations in late gestation increases the growth of offspring; however, there is a lack of evidence on the effect of PUFA supplementation during early gestation. Thus, the objective of this study was to evaluate the effect of dietary supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in early gestation pregnant ewes on fatty acid concentration of fetal liver (FL) and fetal central nervous system (FCNS), and relative abundance of the mRNA for genes associated with transport and metabolism of fatty acids in FL and placenta. A total of 12 ewes, block for stage of gestation were fed a diet containing 1.6% (dry matter basis) monounsaturated fatty acids (MUFA) or EPA+DHA during the first 45 days of gestation. A cesarean section was conducted on day 45 of gestation to collect placenta (caruncle and cotyledon), FL, and FCNS. Relative abundance of mRNA in FL and FCNS and fatty acid concentration were analyzed using a 2x2 factorial arrangement of treatments considering fatty acid supplementation and tissue as the main factors. Concentrations of C18:1 isomers increase (P < 0.05) in FL and FCNS with MUFA supplementation; the FL and FCNS had a greater concentration of C20:3(n-6), C20:3(n-3), C22:1, C22:5 and C22:6 (P < 0.05) with EPA+DHA supplementation. In FL, the relative abundance of LPL mRNA was greater (P = 0.02) as a result of MUFA supplementation. In placenta, there was a FA x tissue interaction for relative abundance of DNMT3b and FFAR-4 mRNA (P < 0.05). Fetus from MUFA-supplemented dams had a greater relative abundance of FABP-4 mRNA (P < 0.05). Results indicate supplementation with EPA+DHA during early gestation increases the total EPA and DHA in FL. For the placenta, EPA+DHA supplementation led to an increase in the relative abundance of lipid mRNA for transport genes.


Assuntos
Sistema Nervoso Central/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos/análise , Feto/efeitos dos fármacos , Placenta/efeitos dos fármacos , RNA Mensageiro/metabolismo , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/química , Feminino , Feto/metabolismo , Idade Gestacional , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Placenta/metabolismo , Gravidez , Ovinos
5.
PLoS One ; 15(4): e0230899, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271776

RESUMO

The domesticated horse has played a unique role in human history, serving not just as a source of animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Completed in 2009, the first domesticated horse reference genome assembly (EquCab 2.0) produced most of the publicly available genetic variations annotations in this species. Yet, there are around 400 geographically and physiologically diverse breeds of horse. To enrich the current collection of genetic variants in the horse, we sequenced whole genomes from six horses of six different breeds: an American Miniature, a Percheron, an Arabian, a Mangalarga Marchador, a Native Mongolian Chakouyi, and a Tennessee Walking Horse, and mapped them to EquCab3.0 genome. Aside from extreme contrasts in body size, these breeds originate from diverse global locations and each possess unique adaptive physiology. A total of 1.3 billion reads were generated for the six horses with coverage between 15x to 24x per horse. After applying rigorous filtration, we identified and functionally annotated 17,514,723 Single Nucleotide Polymorphisms (SNPs), and 1,923,693 Insertions/Deletions (INDELs), as well as an average of 1,540 Copy Number Variations (CNVs) and 3,321 Structural Variations (SVs) per horse. Our results revealed putative functional variants including genes associated with size variation like LCORL gene (found in all horses), ZFAT in the Arabian, American Miniature and Percheron horses and ANKRD1 in the Native Mongolian Chakouyi horse. We detected a copy number variation in the Latherin gene that may be the result of evolutionary selection impacting thermoregulation by sweating, an important component of athleticism and heat tolerance. The newly discovered variants were formatted into user-friendly browser tracks and will provide a foundational database for future studies of the genetic underpinnings of diverse phenotypes within the horse.


Assuntos
Variação Genética , Cavalos/genética , Polimorfismo de Nucleotídeo Único , Animais , Tamanho Corporal/genética , Variações do Número de Cópias de DNA , Proteínas de Ligação a Ácido Graxo/genética , Genoma , Mutação INDEL , Anotação de Sequência Molecular , Sequenciamento Completo do Genoma
6.
Acta Vet Scand ; 62(1): 17, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321549

RESUMO

BACKGROUND: Human obesity is linked with systemic inflammation. However, it is still controversial if equines produce more inflammatory cytokines with increasing body weight and if the production of those show breed type specific patterns. The main objective of this study was to determine if diet induced obesity is associated with increased inflammatory signatures in adipose tissue of equines and if a breed predisposition exists between ponies and horses. Additionally, we aimed to identify adipose tissue depot differences in inflammatory cytokine expression. Nineteen healthy, non-overweight and metabolically healthy equines received a hypercaloric diet for 2 years. Body weight, body condition score and cresty neck score were assessed weekly throughout the study. At three time points, insulin sensitivity was determined by a combined glucose-insulin test. Adipose tissue samples were collected from two intra-abdominal and two subcutaneous depots under general anesthesia at each time point after an endotoxin trigger. In the adipose tissue samples levels of CD68 mRNA (a marker of macrophage infiltration) and pro-inflammatory cytokine mRNA (IL-1ß, IL-6 and TNFα) were analyzed with RT-qPCR. As markers of lipid metabolism mRNA levels of lipoprotein lipase (LPL) and fatty acid binding protein 4 (FABP4) were determined with RT-qPCR. RESULTS: CD68 mRNA levels increased with body weight gain in several adipose tissue (AT) depots (Wilcoxon signed rank test with Bonferroni correction; retroperitoneal AT horses: P = 0.023, mesocolonial AT horses: P = 0.023, subcutaneous tail head AT ponies: P = 0.015). In both abdominal depots CD68 mRNA levels were higher than in subcutaneous adipose tissue depots (Kruskal-Wallis-ANOVA with Bonferroni correction: P < 0.05). No breed related differences were found. Pro-inflammatory cytokine mRNA IL-1ß, IL-6 and TNFα levels were higher in subcutaneous depots compared to abdominal depots after body weight gain. IL-1ß, IL-6 and TNFα mRNA levels of mesocolon adipose tissue were higher in obese horses compared to obese ponies (Mann-Whitney-U test; IL-1ß: P = 0.006; IL-6: P = 0.003; TNFα: P = 0.049). In general, horses had higher FABP4 and LPL mRNA levels compared to ponies in neck AT and tail AT at all time points. CONCLUSION: Our findings suggest an increased invasion of macrophages in intra-abdominal adipose tissue with increasing body weight gain in equines in combination with a low dose endotoxin stimulus. This might predispose equines to obesity related comorbidities. In obese horses mesocolon adipose tissue showed higher inflammatory cytokine expression compared to obese ponies. Additionally, subcutaneous adipose tissue expressed more pro-inflammatory cytokines compared to intra-abdominal adipose tissue. Horses had higher FABP4 and LPL mRNA levels in selected AT depots which may indicate a higher fat storage capacity than in ponies. The differences in lipid storage might be associated with a higher susceptibility to obesity-related comorbidities in ponies in comparison to horses.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Citocinas/genética , Endotoxinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Cavalos/fisiologia , Ganho de Peso/fisiologia , Tecido Adiposo/metabolismo , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Dieta/veterinária , Proteínas de Ligação a Ácido Graxo/genética , Regulação da Expressão Gênica/fisiologia , Lipase Lipoproteica/genética , Obesidade/veterinária , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
7.
Arch Biochem Biophys ; 686: 108365, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32315651

RESUMO

Pelargonidin is a natural compound that exists widely in fruits, and exerts antioxidant, anti-atherosclerotic, anti-inflammatory, anti-hyperglycemic, and anti-diabetic activities. However, there have not been any studies concerning its anti-obesity potential to date. Therefore, we evaluated the anti-obesity potential of pelargonidin via inhibition of adipogenesis in 3T3-L1 cells. The cellular oil droplet content was decreased to 68.14%, 56.75%, and 48.39% and triglyceride accumulation decreased to 74.53%, 61.54%, and 47.86% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin, respectively, when compared with DMSO group. Furthermore, pelargonidin treatment led to decrease in glucose consumption. Western blot assay illustrated that the expression of PPAR-γ was suppressed to 63.25%, 47.52%, and 21.23% after incubation with 5 µM, 10 µM, and 20 µM pelargonidin when compared with DMSO group. Then, we measured the expression of some target proteins of PPAR-γ, and found that pelargonidin decreased the expressions of HMGCR, LPL, Glut4, and A-FABP. Besides, the result of Luciferase Reporter Assay indicated that pelargonidin inhibited PPAR-γ transcription activity. These results indicated that pelargonidin exerts anti-adipogenic activity in 3T3-L1 cells through inhibition of PPAR-γ signaling pathway, and pelargonidin could be used as a potential anti-obesity agent.


Assuntos
Adipogenia/efeitos dos fármacos , Antocianinas/farmacologia , Fármacos Antiobesidade/farmacologia , PPAR gama/metabolismo , Células 3T3-L1 , Animais , Antocianinas/metabolismo , Fármacos Antiobesidade/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Camundongos , Triglicerídeos/genética , Triglicerídeos/metabolismo
8.
Anim Sci J ; 91(1): e13326, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219924

RESUMO

Antibiotics stimulate the growth of animals but result in drug residues and bacterial resistance. In this study, the negative effect of antibiotics on abdominal fat deposition was evaluated in broilers. The results showed that adding both chlortetracycline (50 g/1,000 kg) and tylosin (50 g/1,000 kg) significantly increased abdominal fat weight, abdominal fat percentage (p < .05), and triglyceride and cholesterol levels (p < .05) in blood. Also, both products synchronously stimulated intestinal absorption and synthesis of liver fat. The expression levels of the peroxisome proliferator-activated receptor Î³ (PPARγ), diacylgycerol acyltransferase 2 (DGAT2), lipoprotein lipase (LPL), and fatty acid-binding protein (FABP4) genes in abdominal fat tissue significantly increased (p < .05 or 0.01) when antibiotics were added to the feed. However, no significant difference was found in expression of the fatty acid synthesis (FAS) or acetyl CoA carboxylase (ACC) genes. Further in vitro study results revealed that antibiotics had no effect on fat content or the related gene expression levels in preadipocytes. In summary, the antibiotics induced fat deposition in adipose tissues by activating extracellular absorption of fatty acids from intestinal absorption and synthesis of liver fat. However, it shows no direct regulation by adipose tissue.


Assuntos
Gordura Abdominal/metabolismo , Antibacterianos/farmacologia , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Clortetraciclina/farmacologia , Tilosina/farmacologia , Tecido Adiposo/metabolismo , Animais , Antibacterianos/efeitos adversos , Clortetraciclina/efeitos adversos , Colesterol/sangue , Diacilglicerol O-Aciltransferase/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica , Absorção Intestinal , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Triglicerídeos/sangue , Tilosina/efeitos adversos
9.
J Med Food ; 23(3): 281-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32119806

RESUMO

The aim of this study was to investigate the effect of a high-fat diet (HFD) on energy substrate utilization during long-term endurance exercise in mice. Male ICR mice (n = 32; 6 weeks old) were divided into two groups: low-fat diet (LFD, n = 16) and HFD (n = 16) and acclimatized to LFD or HFD feeding over 12 weeks. After 12 weeks, the two dietary groups were each divided into two groups with or without exercise (EX): LF-CON, LF-EX, HF-CON, and HF-EX groups. The exercise groups were trained to run on a treadmill for 12 weeks. At the end of the experimental protocol, energy metabolism in the whole body was measured at rest for 24 h and during exercise for 1 h using respiratory gas analysis. Furthermore, molecules involved in skeletal muscle fat metabolism were analyzed. Substrate utilization for energy metabolism in the whole body indicated that fat utilization was high in HFD intake. Notably, when HFD intake and exercise were combined, fat utilization was markedly increased during endurance exercise. In contrast, exercise showed no effect when combined with LFD intake. The gene expressions of Fat/Cd36, Fatp1, Fabp-pm, and Cpt1 were upregulated by HFD intake, with Fat/Cd36 and Cpt1 considerably elevated during long-term endurance exercise. In contrast, exercise showed no effect when combined with LFD intake. These results suggest that HFD intake effectively increased fat utilization as an energy substrate during long-term endurance exercise.


Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Músculo Esquelético/metabolismo , Animais , Dieta Hiperlipídica , Gorduras na Dieta/análise , Metabolismo Energético , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Oxirredução , Condicionamento Físico Animal
10.
Parasitol Res ; 119(4): 1401-1408, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32130486

RESUMO

Fatty acid-binding proteins (FABPs) are small intracellular proteins that reversibly bind fatty acids and other hydrophobic ligands. In cestodes, due to their inability to synthesise fatty acids de novo, FABPs have been proposed as essential proteins, and thus, as possible drug targets and/or carriers against these parasites. We performed data mining in Echinococcus multilocularis and Echinococcus granulosus genomes in order to test whether this family of proteins is more complex than previously reported. By exploring the genomes of E. multilocularis and E. granulosus, six genes coding for FABPs were found in each organism. In the case of E. granulosus, all of them have different coding sequences, whereas in E. multilocularis, two of the genes code for the same protein. Remarkably, one of the genes (in both cestodes) encodes a FABP with a C-terminal extension unusual for this family of proteins. The newly described genes present variations in their structure in comparison with previously described FABP genes in Echinococcus spp. The coding sequences for E. multilocularis were validated by cloning and sequencing. Moreover, differential expression patterns of FABPs were observed at different stages of the life cycle of E. multilocularis by exploring transcriptomic data from several sources. In summary, FABP family in cestodes is far more complex than previously thought and includes new members that seem to be only present in flatworms.


Assuntos
Echinococcus granulosus/genética , Echinococcus multilocularis/genética , Proteínas de Ligação a Ácido Graxo/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , DNA de Protozoário/genética , Ácidos Graxos/metabolismo , Genoma de Protozoário/genética , Análise de Sequência , Análise de Sequência de DNA , Transcriptoma/genética
11.
Gene ; 741: 144516, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32119914

RESUMO

To study the influence of the PGC-1ß gene on chicken adipocyte proliferation and differentiation, we constructed RNA interference (RNAi) vectors that target the PGC-1ß gene and transfected these vectors into adipocytes. Oil Red O staining and a CCK-8 cell kit were used to determine cell triglyceride accumulation status and cell proliferation after transfection, respectively. The mRNA abundances of PGC-1ß and adipocyte-differentiation-related genes (PPARγ, C/EBPα, SREBP-1c, FAS, and A-FABP) were detected by real-time PCR. The results showed that the mRNA and protein abundances of PGC-1ß in PGC-1ß-shRNA transfected adipocytes were significantly lower than those in the control. Interference decreased cell differentiation, but did not depress the cell proliferation. PGC-1ß interference impeded the triglyceride accumulation, the mRNA expression levels of nuclear receptors PPARγ and SREBP-1c, and fatty acid synthetase (FAS), and both proteins PPARγ and SREBP-1c, and the fatty acids transporting protein A-FABP. Generally, PGC-1ß modulated the cell differentiation and triglyceride accumulation in chicken adipocytes.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , Receptores Ativados por Proliferador de Peroxissomo/genética , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proliferação de Células/genética , Galinhas/genética , Galinhas/crescimento & desenvolvimento , Ácido Graxo Sintases/genética , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , PPAR gama/genética , RNA Mensageiro , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo , Receptor fas/genética
12.
Cancer Res ; 80(8): 1748-1761, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32054768

RESUMO

Adipocytes are critical for ovarian cancer cells to home to the omentum, but the metabolic changes initiated by this interaction are unknown. To this end, we carried out unbiased mass spectrometry-based metabolomic and proteomic profiling of cancer cells cocultured with primary human omental adipocytes. Cancer cells underwent significant proteo-metabolomic alteration(s), typified by changes in the lipidome with corresponding upregulation of lipid metabolism proteins. FABP4, a lipid chaperone protein, was identified as the critical regulator of lipid responses in ovarian cancer cells cocultured with adipocytes. Subsequently, knockdown of FABP4 resulted in increased 5-hydroxymethylcytosine levels in the DNA, downregulation of gene signatures associated with ovarian cancer metastasis, and reduced clonogenic cancer cell survival. In addition, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated knockout of FABP4 in high-grade serous ovarian cancer cells reduced metastatic tumor burden in mice. Consequently, a small-molecule inhibitor of FABP4 (BMS309403) not only significantly reduced tumor burden in a syngeneic orthotopic mouse model but also increased the sensitivity of cancer cells toward carboplatin both in vitro and in vivo. Taken together, these results show that targeting FABP4 in ovarian cancer cells can inhibit their ability to adapt and colonize lipid-rich tumor microenvironments, providing an opportunity for specific metabolic targeting of ovarian cancer metastasis. SIGNIFICANCE: Ovarian cancer metastatic progression can be restricted by targeting a critical regulator of lipid responses, FABP4.


Assuntos
Adipócitos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Ligação a Ácido Graxo/metabolismo , Neoplasias Ovarianas/metabolismo , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/análise , Animais , Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Carboplatina/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Técnicas de Cocultura , Metilação de DNA , Regulação para Baixo , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Metabolismo dos Lipídeos , Lipidômica , Espectrometria de Massas , Metabolômica/métodos , Camundongos , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Omento/citologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Análise Serial de Proteínas , Proteômica/métodos , Pirazóis/farmacologia , Carga Tumoral/efeitos dos fármacos , Regulação para Cima
13.
Br Poult Sci ; 61(3): 232-241, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32063032

RESUMO

1. Fatty acid-binding proteins (FABP) are members of lipid-binding proteins, which participate in the metabolism and intracellular transportation of lipids. This study was designed to investigate the expression patterns, polymorphisms and associations with meat quality traits of the FABP1 gene in pigeons. 2. The temporal-spatial expression patterns showed FABP1 was widely expressed in all eleven tissues from 0-4 weeks of age, the expression level in the liver was the highest, followed by the small intestine and subcutaneous fat. 3. Five novel SNPs were found; all of them were synonymous and in Hardy-Weinberg equilibrium. Association analysis revealed that for the SNP of G161C, the AB and BB genotypes had higher (P ≤ 0.01) inosinic acid concentrations in breast muscle than the AA genotype. The BB genotype showed the highest (P < 0.01) intramuscular fat among the three genotypes, and significantly greater FABP1 mRNA levels were observed in the breast muscle of the BB genotype than in the AA and AB genotypes (P < 0.01). In the SNP C1376T, the AB and BB genotypes showed higher (P < 0.01) intramuscular fat than the AA genotype, and the relative mRNA expression level of the BB (P < 0.01) and AB (P < 0.05) genotypes was higher than that of the AA genotype in breast muscle. Correlation analysis implied that the FABP1 mRNA expression level was closely related to the inosinic acid (P < 0.05) and intramuscular fat content (P < 0.01). Oil red O staining of frozen sections of breast muscle on d 28 for SNPs G161C and C1376T also indicated that the BB genotype had the highest intramuscular fat content in both SNPs. In addition, correlation analysis implied the FABP1 mRNA expression level was closely related to inosinic acid (P < 0.05) and intramuscular fat content (P < 0.01). 4. The results suggested that FABP1 could be a potential candidate gene in marker-assisted selection for breeding pigeons with high-quality meat.


Assuntos
Columbidae , Proteínas de Ligação a Ácido Graxo , Animais , Proteínas de Ligação a Ácido Graxo/genética , Frequência do Gene , Genótipo , Carne , Fenótipo , Polimorfismo de Nucleotídeo Único
14.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.


Assuntos
Complexo II de Transporte de Elétrons/metabolismo , Gorduras/metabolismo , Obesidade/enzimologia , Estearoil-CoA Dessaturase/genética , Ácido Succínico/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipogenia , Animais , Metabolismo Energético , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Estearoil-CoA Dessaturase/metabolismo , Termogênese
15.
Adipocyte ; 9(1): 35-50, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31996081

RESUMO

Adipocyte differentiation of bovine adipose-derived stem cells (ASC) was induced by foetal bovine serum (FBS), biotin, pantothenic acid, insulin, rosiglitazone, dexamethasone and 3-isobutyl-1-methylxanthine, followed by incubation in different media to test the influence of ascorbic acid (AsA), bovine serum lipids (BSL), FBS, glucose and acetic acid on transdifferentiation into functional adipocytes. Moreover, different culture plate coatings (collagen-A, gelatin-A or poly-L-lysine) were tested. The differentiated ASC were subjected to Nile red staining, DAPI staining, immunocytochemistry and quantitative reverse transcription PCR (for NT5E, THY1, ENG, PDGFRα, FABP4, PPARγ, LPL, FAS, GLUT4). Nile red quantification showed a significant increase in the development of lipid droplets in treatments with AsA and BSL without FBS. The presence of BSL induced a prominent increase in FABP4 mRNA abundance and in FABP4 immunofluorescence signals in coincubation with AsA. The abundance of NT5E, ENG and THY1 mRNA decreased or tended to decrease in the absence of FBS, and ENG was additionally suppressed by AsA. DAPI fluorescence was higher in cells cultured in poly-L-lysine or gelatin-A coated wells. In additional experiments, the multi-lineage differentiation potential to osteoblasts was verified in medium containing ß-glycerophosphate, dexamethasone and 1,25-dihydroxyvitamin D3 using alizarin red staining. In conclusion, bovine ASC are capable of multi-lineage differentiation. Poly-L-lysine or gelatin-A coating, the absence of FBS, and the presence of BSL and AsA favour optimal transdifferentiation into adipocytes. AsA supports transdifferentiation via a unique role in FABP4 induction, but this is not linearly related to the primarily BSL-driven lipid accumulation.Abbreviations: AcA: acetic acid; AsA: ascorbic acid; ASC: adipose-derived stem cells; BSL: bovine serum lipids; DAPI: 4´,6-diamidino-2-phenylindole; DLK: delta like non-canonical notch ligand; DMEM: Dulbecco's modified Eagle's medium; DPBS: Dulbecco's phosphate-buffered saline; ENG: endoglin; FABP: fatty acid binding protein; FAS: fatty acid synthase; GLUT4: glucose transporter type 4; IBMX: 3-isobutyl-1-methylxanthine; LPL: lipoprotein lipase; MSC: mesenchymal stem cells; α-MEM: α minimum essential medium; NT5E: ecto-5'-nucleotidase; PDGFRα: platelet derived growth factor receptor α; PPARγ: peroxisome proliferator activated receptor γ; RPS19: ribosomal protein S19; SEM: standard error of the mean; THY1: Thy-1 cell surface antigen; TRT: treatment; TRT-Con: treatment negative control; YWHAZ: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta.


Assuntos
Ácido Ascórbico/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Células-Tronco Mesenquimais/citologia , Animais , Bovinos , Diferenciação Celular , Transdiferenciação Celular , Células Cultivadas , Meios de Cultura/química , Regulação da Expressão Gênica/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Regulação para Cima
16.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G518-G530, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905021

RESUMO

Intestinal-fatty acid binding protein (IFABP; FABP2) is a 15-kDa intracellular protein abundantly present in the cytosol of the small intestinal (SI) enterocyte. High-fat (HF) feeding of IFABP-/- mice resulted in reduced weight gain and fat mass relative to wild-type (WT) mice. Here, we examined intestinal properties that may underlie the observed lean phenotype of high fat-fed IFABP-/- mice. No alterations in fecal lipid content were found, suggesting that the IFABP-/- mice are not malabsorbing dietary fat. However, the total excreted fecal mass, normalized to food intake, was increased for the IFABP-/- mice relative to WT mice. Moreover, intestinal transit time was more rapid in the IFABP-/- mice. IFABP-/- mice displayed a shortened average villus length, a thinner muscularis layer, reduced goblet cell density, and reduced Paneth cell abundance. The number of proliferating cells in the crypts of IFABP-/- mice did not differ from that of WT mice, suggesting that the blunt villi phenotype is not due to alterations in proliferation. IFABP-/- mice were observed to have altered expression of genes and proteins related to intestinal structure, while immunohistochemical analyses revealed increased staining for markers of inflammation. Taken together, these studies indicate that the ablation of IFABP, coupled with high-fat feeding, leads to changes in gut motility and morphology, which likely contribute to the relatively leaner phenotype occurring at the whole-body level. Thus, IFABP is likely involved in dietary lipid sensing and signaling, influencing intestinal motility, intestinal structure, and nutrient absorption, thereby impacting systemic energy metabolism.NEW & NOTEWORTHY Intestinal fatty acid binding protein (IFABP) is thought to be essential for the efficient uptake and trafficking of dietary fatty acids. In this study, we demonstrate that high-fat-fed IFABP-/- mice have an increased fecal output and are likely malabsorbing other nutrients in addition to lipid. Furthermore, we observe that the ablation of IFABP leads to marked alterations in intestinal morphology and secretory cell abundance.


Assuntos
Adiposidade , Dieta Hiperlipídica , Proteínas de Ligação a Ácido Graxo/deficiência , Motilidade Gastrointestinal , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Ganho de Peso , Animais , Morte Celular , Defecação , Metabolismo Energético , Enterócitos/metabolismo , Enterócitos/patologia , Proteínas de Ligação a Ácido Graxo/genética , Fezes/química , Deleção de Genes , Genótipo , Absorção Intestinal , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Intestino Delgado/patologia , Intestino Delgado/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fatores de Tempo
17.
Appl Microbiol Biotechnol ; 104(5): 2149-2161, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31950220

RESUMO

Fatty acid-binding protein 2 (Fabp2), which is involved in the transport of long-chain fatty acids, is widely studied in mammals. Nevertheless, the role of this protein in teleost fish is mostly unknown. Here, we produced a fabp2-/- zebrafish (KO) animal model. Compared with wild-type zebrafish (WT), KO had a markedly decreased content of intestinal n-3 poly-unsaturated fatty acids (n-3 PUFAs) and increased levels of intestinal, hepatic, and serum triacylglycerols (TAG). The intestinal transcriptome analysis of KO and WT revealed an obviously disrupted TAG metabolism and up-regulated bile secretion in KO. Expression levels of the genes related to fatty acid transport and cholesterol (CL) absorption in the intestine of KO were significantly lower than those of WT, while the expression levels of genes related to intestinal TAG synthesis and hepatic CL synthesis were in the opposite direction. To confirm these findings, we further established fabp2 transgenic zebrafish (TG). Compared with WT, TG had a markedly increased content of intestinal n-3 PUFAs, a significantly decreased level of hepatic TAG, and significantly higher expression of genes related to fatty acid transport and CL absorption in the intestine. In conclusion, this study suggests that teleost fish fabp2 could promote intestinal n-3 PUFA absorption to mediate TAG synthesis and CL homeostasis, by regulating the genes involved in lipid metabolism.


Assuntos
Colesterol/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos Ômega-3/metabolismo , Deleção de Genes , Triglicerídeos/metabolismo , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Ácidos e Sais Biliares/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Homeostase , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
18.
Cardiovasc Pathol ; 46: 107192, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31927390

RESUMO

BACKGROUND: Cytoplasmic fatty acid-binding proteins facilitate the transport of lipids to specific compartments in cells. Fatty acid-binding protein 4 (FABP4), also known as aP2 or A-FABP, plays a key role in the development of atherosclerosis, insulin resistance, obesity, and metabolic syndrome (MS). The FABP4 polymorphisms are associated with protein expression changes in vitro and metabolic and vascular alterations in vivo. The aim of this study was to investigate the association between FABP4 messenger ribonucleic acid (mRNA) expression levels in epicardial (EAT), pericardial (PAT), and subcutaneous adipose tissues (SAT), and the extent of coronary atherosclerosis in coronary artery disease (CAD) patients with MS. Furthermore, the relationship between the extent of coronary atherosclerosis and epicardial adipose tissue volume (EATV) and FABP4 gene variations was evaluated. PATIENTS AND METHODS: A total of 37 patients undergoing coronary artery bypass grafting because of CAD (MS CAD group) and 23 non-MS patients undergoing heart valve surgery (control group) were included. Coronary angiography was performed for all patients and the extent of coronary atherosclerosis was assessed using the Sullivan's scoring system. The mRNA expression levels of FABP4 gene in EAT, PAT, and SAT, and FABP4 polymorphisms were analyzed using the quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: An increased FABP4 expression was observed in EAT and PAT of MS CAD group compared to controls. In the MS CAD group, FABP4 mRNA expression levels in EAT was 2.8-fold higher compared to PAT. The expression of FABP4 in EAT was positively correlated with the extent of atherosclerosis and EATV in MS CAD group (r = 0.588, P= 0.001, r = 0.174, P = 0.001, respectively). There were no correlations between PAT and SAT versus the extent of atherosclerosis and EATV. The FABP4 EAT mRNA expression levels were found to significantly increase in mutant allele carriers of rs1054135, whereas they significantly decreased in mutant allele carriers of rs77878271 (T-87C) in MS CAD group (P < 0.05). The extent of atherosclerosis was also found to be significantly associated with rs1054135 (P < 0.05). A cut-off point of 57.5 cm3 EATV was used indicating the presence of CAD with a significant area under the curve of 0.783%, 98% sensitivity, and 100% specificity (95% CI 0.620-0.880; P < 0.05). CONCLUSIONS: Our study results suggest that FABP4 expression in EAT is strongly associated with the extent of atherosclerosis and EATV in MS CAD patients.


Assuntos
Doença da Artéria Coronariana/genética , Proteínas de Ligação a Ácido Graxo/genética , Gordura Intra-Abdominal/química , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Gordura Subcutânea/química , Idoso , Estudos de Casos e Controles , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Predisposição Genética para Doença , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Masculino , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Fenótipo , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Índice de Gravidade de Doença , Gordura Subcutânea/diagnóstico por imagem
19.
PLoS One ; 15(1): e0227067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931521

RESUMO

BACKGROUND: Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity. METHODS: We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF. RESULTS: The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins. CONCLUSIONS: BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.


Assuntos
Fibrose Cística/genética , Genes Modificadores , Glicoproteínas/genética , Fosfoproteínas/genética , Pneumonia/genética , Autoantígenos/genética , Autoantígenos/metabolismo , Linhagem Celular , Fibrose Cística/complicações , Fibrose Cística/imunologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Glicoproteínas/metabolismo , Humanos , Fosfoproteínas/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Polimorfismo de Nucleotídeo Único , Mucosa Respiratória/imunologia
20.
Environ Toxicol ; 35(2): 203-212, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31714650

RESUMO

The incidence of type 1 diabetes (T1D) and its associated risks of chronic kidney disease or end-stage renal disease development are on the rise. T1D is an autoimmune disease in which insulin-producing beta cells are destroyed. Increased incidence of T1D has been suggested to be a result of environmental factors such as exposure to polycyclic aromatic hydrocarbons (PAHs). 2-aminoanthracene (2AA) is a PAH that has been associated with the onset of early diabetic symptoms. This study was conducted to assess if 2AA dietary ingestion would induce T1D renal injuries. To accomplish study goals, Sprague-Dawley rats were assigned into three 2AA dietary (0, 50, and 100 mg/kg-2AA) ingestion groups for 12 weeks. Animals were evaluated for various morphometric indices, clinical markers, and gene expression. The rats in the 100 mg/kg group lost 5% less weight than the other treatment groups and converted roughly 3% more of their food intake into body mass. Renal histopathology indicated no significant difference between groups. The kidney weight per bodyweight of the 100 mg/kg treatment group was 30.1% greater than the control group. Creatinine concentration of the 100 mg/kg group was 46.2% greater than the control group. Serum glucose levels were significantly elevated in rats exposed to 2AA. On the contrary, serum albumin concentration was significantly reduced in 2AA-treated rats. T1D and genetic markers of renal injury such as FABP1, SPP1, IL-1B, and IL-7 were elevated in treated groups. These results suggest that 2AA may induce the early diabetic renal injuries.


Assuntos
Antracenos/toxicidade , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Rim/efeitos dos fármacos , Animais , Biomarcadores/sangue , Glicemia/análise , Creatinina/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 1/sangue , Proteínas de Ligação a Ácido Graxo/genética , Rim/metabolismo , Rim/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Albumina Sérica/análise
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